Methods for treating antipsychotic-induced weight gain

ABSTRACT

The present invention relates to the discovery of a novel opioid modulator effective in reducing pharmacologically induced weight gain associated with atypical antipsychotic use. The present invention provides methods of reducing antipsychotic induced weight gain, methods for suppressing food intake and reducing ghrelin levels induced by atypical antipsychotic medications in a patient.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/899,708, filed Jun. 12, 2020, which is a continuation of U.S.application Ser. No. 16/390,531, filed Apr. 22, 2019, now U.S. Pat. No.10,716,785, issued Jul. 21, 2020, which is a divisional of U.S.application Ser. No. 15/923,084, filed Mar. 16, 2018, now U.S. Pat. No.10,300,054, issued May 28, 2019 which is a continuation of U.S.application Ser. No. 15/342,263, filed Nov. 3, 2016, now U.S. Pat. No.9,943,514, issued Apr. 17, 2018 which is a continuation of U.S.application Ser. No. 14/813,260, filed Jul. 30, 2015, now U.S. Pat. No.9,517,235, issued Dec. 13, 2016, which is a continuation of U.S.application Ser. No. 14/297,171, filed Jun. 5, 2014, now U.S. Pat. No.9,126,977, issued Sep. 8, 2015, which is a continuation of U.S.application Ser. No. 13/215,718, filed Aug. 23, 2011, now U.S. Pat. No.8,778,960, issued Jul. 15, 2014, which claims the benefit of U.S.Provisional Application No. 61/376,120, filed on Aug. 23, 2010. Theentire teachings of the above applications are incorporated herein byreference.

FIELD OF INVENTION

The present invention relates to medications used for weight control.More particularly, the present invention relates to the use of a novelopioid receptor modulator to minimize weight gain associated withantipsychotic drugs.

BACKGROUND OF INVENTION

Antipsychotic medications are among the most important therapeutic toolsfor treating various psychotic disorders. There are two categories ofantipsychotics, typical and atypical. Typical antipsychotics e.g.,haloperidol and chlorpromazine, were first developed in the 1950's andwere used to treat psychosis, particularly schizophrenia. Common sideeffects of typical antipsychotics include: dry mouth, tremors, weightgain, muscle tremors, and stiffness. In addition, typical antipsychoticsyield extrapyramidal side effects. These side effects include: motordisturbances, parkinsonian effects, akathesia, dystonia, akinesia,tardive dyskinesia, and neuroleptic malignant syndrome. Some of theseside effects have been described to be worse than the actual symptoms ofschizophrenia. Atypical antipsychotics are considered to be the firstline of treatment for schizophrenia because of the improvedextrapyramidal side effect profile in comparison to typicalantipsychotics. Atypical antipsychotics are also associated withsuperior tolerability, adherence and relapse prevention and have led toimproved treatment for patients with serious mental illness. However,they are also associated with significant weight gain. Numerous reportsbased on extensive clinical studies have reported that 40-80% ofpatients under chronic atypical antipsychotic treatment experiencesubstantial weight gain, ultimately exceeding their ideal body weight by20% (Umbricht et al., J Clin. Psychiatry 55 (Suppl. B):157-160;Baptista, Acta Psychiatr. Scand. 100:3-16, 1999). Weight gain was foundto be greatest with clozapine, olanzapine, risperidone, and quetiapine,and less with aripiprazole and ziprasidone. (Taylor et al., ActaPsychiatr Scand. 2001 February; 103(2):158). Weight gain associated withatypical antipsychotics increases the risk of obesity in patientsundergoing treatment. Obesity is a leading cause of mortality as itfrequently leads to conditions such as diabetes and cardiovasculardisorders. In addition, atypical antipsychotics are increasinglyprescribed to children and adolescents with psychiatric disorders. Arecent study reported that young children who take antipsychotics risklong term health risks associated with rapid weight gain, for example,metabolic changes that could lead to diabetes, hypertension and otherillnesses. (Varley et al., JAMA. 2009; 302(16):1811-1812).

Excessive weight gain associated with atypical antipsychotic use is asignificant issue given its impact on general health and psychologicalissues. Unwanted weight gain is also one of the most common reasons fora patient's non-compliance of an atypical antipsychotic administrationschedule, ultimately leading to the failure of the treatment. Therefore,there is a continuing need to identify and develop more effective drugtreatments for preventing or reducing this side effect of atypicaltreatment.

SUMMARY OF INVENTION

Applicants have surprisingly discovered that compounds of Formula I areeffective in reducing pharmacologically induced weight gain associatedwith atypical antipsychotic use.

wherein,A is chosen from —C(═O)NH₂ and —C(═S)NH₂;R¹ and R² are both hydrogen or taken together R¹ and R² are ═O;R³ is chosen from hydrogen, alkyl, alkenyl, aryl, heterocyclyl andhydroxyalkyl;R⁴ is chosen from hydrogen, hydroxy, amino, alkoxy, C₁-C₂₀ alkyl andC₁-C₂₀ alkyl substituted with hydroxy or carbonyl;R⁵ is selected from hydrogen, hydroxyl, alkoxy and alkyl;R⁶ is chosen from hydrogen, hydroxy, alkoxy and —NR¹⁰R¹¹;or together, R⁵ and R⁶ form a carbonyl or a vinyl substituent;R¹⁰ and R¹¹ are chosen independently from hydrogen, alkyl and aliphatic;and,

represents a single or double bond.

As such, the present invention provides methods of reducingantipsychotic induced weight gain induced by atypical antipsychoticmedications in a patient. The method comprises administration of atherapeutically effective amount of a compound of Formula I to thepatient in need thereof, preferably, Compound 1.

In one aspect, the invention relates to the lowering of circulatingghrelin levels and/or the levels of ghrelin in gastrointestinal tracts.As such, the present invention is further directed to methods ofsuppressing food intake comprising administering to the patient in needof treatment an effective amount of the compounds of Formula I, whereinthe increased appetite is induced by administration of an atypicalantipsychotic.

In one embodiment, the induced weight gain is associated withadministration of olanzapine, clozapine, risperidone, quetiapine,aripiprazole, ziprasidone, and pharmaceutically acceptable saltsthereof. In one aspect, the patient undergoing treatment is sufferingfrom schizophrenia, bipolar disorder, acute mania, major depression orpsychotic agitation or palliative care or is in need of terminalsedation.

In another embodiment, the compounds of Formula I are administeredorally to the patient in need of treatment at a daily dose of about 3 to30 mg/day, more preferably about 3 to 15 mg/day, even more preferably 5mg/day. In another aspect, the compounds of Formula I are administeredprior to the administration of an atypical antipsychotic or after theadministration of an atypical antipsychotic, or along with theadministration of an atypical antipsychotic or prior to the onset of theantipsychotic induced weight gain or at the start of the patient'satypical antipsychotic treatment. In one embodiment, the compounds ofFormula I are administered daily. In some embodiments, the patientreceiving daily administration of a compound of Formula I also receivesa daily administration of an atypical antipsychotic.

In still another embodiment, the patient within the past week, month oryear of atypical antipsychotic treatment has gained about 5, 10, 15, or20% body weight.

In another embodiment, the invention relates to a composition comprisinga compound of Formula I and an antipsychotic, preferably selected fromolanzapine, clozapine, risperidone, quetiapine, aripiprazole andziprasidone.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: Evaluation of Compound 1 on olanzapine-related weight gain infemale rats. Mean cumulative weight gain of female rats on olanzapinealone, naltrexone+olanzapine and Compound 1+olanzapine as a function ofdays is shown.

FIG. 2: Evaluation of Compound 1 and naltrexone on circulating ghrelinlevels (pg/mL) as a function of time (hours) is shown.

FIG. 3: Evaluation of olanzapine induced weight gain and bodycomposition in female cynomolgus monkeys treated with and withoutCompound 1.

FIG. 4: Change in fat distribution for female cynomolgus monkeysadministered with olanzapine with and without Compound 1.

FIG. 5: (a) CT scan evaluation of olanzapine induced weight gain onabdominal fat distribution in female cynomolgus monkeys treated witholanzapine; (b) CT scan evaluation of olanzapine induced weight gain onabdominal fat distribution in female cynomolgus monkeys treated witholanzapine and Compound 1.

FIG. 6: Evaluation of blood serum chemistry analysis on femalecynomolgus monkeys treated with and without Compound 1.

DETAILED DESCRIPTION OF INVENTION

The present invention relates to compounds of Formula I:

wherein, A is chosen from —C(═O)NH₂ and —C(═S)NH₂;R¹ and R² are both hydrogen or taken together R¹ and R² are ═O;R³ is chosen from hydrogen, alkyl, alkenyl, aryl, heterocyclyl andhydroxyalkyl;R⁴ is chosen from hydrogen, hydroxy, amino, alkoxy, C₁-C₂₀ alkyl andC₁-C₂₀ alkyl substituted with hydroxy or carbonyl;R⁵ is selected from hydrogen, hydroxyl, alkoxy and alkyl;R⁶ is chosen from hydrogen, hydroxy, alkoxy and —NR¹⁰R¹¹;or together, R⁵ and R⁶ form a carbonyl or a vinyl substituent;R¹⁰ and R¹¹ are chosen independently from hydrogen, alkyl and aliphatic;and

represents a single or double bond.

In a preferred embodiment, compounds of the invention are related tocompounds of Formula II:

wherein, R³, R⁴, R⁵, and R⁶ are as defined above.

A more preferred embodiment is a compound of Formula I or II wherein,

R⁴ is selected from hydrogen and hydroxyl;R⁵ is selected from hydrogen, and hydroxyl; and,R⁶ is hydrogen;or together, R⁵ and R⁶ form a carbonyl or a vinyl substituent.

A more preferred embodiment is a compound of Formula I or II, wherein R³is selected from, hydrogen, cyclopropyl, cyclobutyl, vinyl, furan andtetrahydrofuran.

In a preferred embodiment, compounds of the invention are selected fromTable A:

TABLE A  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

Antipsychotic drug therapy is a fundamental tool in the treatment ofschizophrenia, bipolar disorder, dementia, acute mania, majordepression, psychotic agitation and several non-psychotic mental andneurological conditions. Excessive body weight gain was reported duringthe 1950's as an adverse effect of typical antipsychotic drug treatment,but the magnitude of body weight gain was found to be higher with theatypical antipsychotic drugs that were introduced after 1990. Atypicalantipsychotic drugs such as aripiprazole, clozapine, olanzapine,risperidone, quetiapine, ziprasidone, amusulpride, zotepine andseritindole convey fewer neurological adverse side effects than thetypical agents, however, the adverse bodyweight gain associated withatypical treatment has a negative impact on other components of themetabolic profile, such as serum glucose levels, triglyceride andhigh-density cholesterol levels. The mechanisms by which atypicalantipsychotic drugs cause weight gain are not clear. Atypicalantipsychotic drugs may increase appetite stimulation by eithermodifying the function of the appetite system i.e., indices of satietyor by targeting neurochemical physiology and metabolic function i.e.,modulation of known hormone targets involved in appetite regulation,such as leptin and ghrelin.

Applicants have surprisingly discovered that compounds of Formula I, agroup of opioid modulators are effective in reducing pharmacologicallyinduced weight gain associated with atypical antipsychotic use. As usedherein, the term “opioid modulator” refers to compounds that can act asan agonist, antagonist or partial agonist at opioid receptors throughoutthe body. In one aspect, some of the compounds of Formula I, inparticular Compound 1, acts as a mu-opioid receptor antagonist andpartial agonist/antagonist at kappa and delta receptors.

As used herein, the term “reducing” refers to any indicia of success inthe prevention or reduction of weight gain in a patient induced by anatypical antipsychotic medication. The prevention or reduction ofatypical-induced weight gain can be measured based on objectiveparameters, such as the results of a physical examination. For example,patients undergoing atypical antipsychotic treatment were able tomaintain a healthful weight range when given Compound 1. As used herein,a “healthful weight range” refers to a body mass index (BMI) between 19and 25, as defined by the first Federal guidelines on theidentification, evaluation, and treatment of overweight and obesitydeveloped by the National Heart, Lung, and Blood Institute, incooperation with the National Institute of Diabetes and Digestive andKidney Diseases (Clinical Guidelines on the Identification, Evaluation,and Treatment of Overweight and Obesity in Adults: Evidence Report,1998).

Weight gain as a result of prolonged atypical treatment can bedetermined based on comparison of changes in a patient's body weightduring the course of treatment. The weight gained may also be reflectedin an increased body fat percentage. To be considered to have gainedweight as a result of atypical treatment, weight gain may be measured bya percentage increase in weight during atypical treatment, e.g., anincrease of body weight by at least 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%or 40%, over, for example, a ten-week period of atypical treatment. Anincrease in body fat percentage may also be used to measure weight gain,e.g., an increase of body fat percentage by at least 2%, 5%, 10%, or 15%over, for example, a ten-week period of atypical treatment. Weight gainas a result of atypical treatment can occur as soon as the patientbegins the atypical treatment regime i.e., within days or weeks or theperiod can be more prolonged i.e., months or within a year.

As used herein, the term “atypical” refers to the newer class ofantipsychotic agents that have reduced extrapyramidal side effects incomparison with traditional antipsychotic medications such aschloropromazine, loxapine, haloperidol, fluphenazine, etc. Examples ofsuch atypical antipsychotics include, but are not limited to,amisulpride, aripiprazole, asenapine, blonanserin, bifeprunox,clotiapine, clozapine, iloperidone, lurasidone, mosapramine, melperone,olanzapine, paliperidone, perospirone, pimavanserin, quepin, quetiapine,remoxipride, risperidone, sertindole, sulpiride, vabicaserin,ziprasidone, and zotepine.

Compounds of Formula I are particularly useful for the treatment ofweight gain associated with atypical antipsychotics, including, but arenot limited to, amisulpride, aripiprazole, asenapine, blonanserin,bifeprunox, clotiapine, clozapine, iloperidone, lurasidone, mosapramine,melperone, olanzapine, paliperidone, perospirone, pimavanserin, quepin,quetiapine, remoxipride, risperidone, sertindole, sulpiride,vabicaserin, ziprasidone, and zotepine. It is understood that thepresent invention includes all pharmaceutically acceptable salts,hydrates, solvates, and polymorphs of the above drugs in combinationwith compounds of Formula I and its salts, hydrates, solvates andpolymorphs.

Preferred atypical antipsychotics of the present invention include:Olanzapine,2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,and its preferred crystal form II is a known compound and is describedin U.S. Pat. Nos. 5,229,382 and 5,736, 541 as being useful in thetreatment of schizophrenia, schizophreniform disorder, acute mania, mildanxiety states, and psychosis.

Clozapine,8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, isdescribed in U.S. Pat. No. 3,539,573. Clinical efficacy in the treatmentof schizophrenia is described in (Hanes, et al, Psychopharmacol. Bull.,24, 62 (1988)).

Risperidone,4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one,and its use in the treatment of psychotic diseases are described in U.S.Pat. No. 4,804,663.

Quetiapine,2-(2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol,and its activity in assays, which demonstrate utility in the treatmentof schizophrenia are described in U.S. Pat. No. 4,879,288. Quetiapine istypically administered as its (E)-2-butenedioate (2:1) salt.

Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl) piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one and its utility in the treatmentof schizophrenia are described in U.S. Pat. No. 5,006,528.

Ziprasidone,5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one,is typically administered as the hydrochloride monohydrate. The compoundis described in U.S. Pat. Nos., 4,831,031 and 5,312,925. Its activity inassays which demonstrate utility in the treatment of schizophrenia aredescribed in U.S. Pat. No. 4,831,031.

The patient, as used herein is preferably a mammal, with human patientsespecially preferred, is suffering from a mental illness treatable withan atypical antipsychotic medication. Typical disease states treatablewith antipsychotic medication include, but are not limited to,schizophreniform disorder, schizoaffective disorder, severeschizoaffective disorder with psychotic features, bipolar I disorderswith a single manic episode, severe bipolar I disorders with psychoticfeatures, bipolar I disorders manifesting a mixed most recent episode,severe bipolar I disorders with psychotic features, brief psychoticdisorders, psychotic disorders NOS, paranoid personality disorders,schizoid personality disorders, schizophrenia, schizotypal personalitydisorders with sedative, hypnotic, or anxiolytic manifestations, majordepressive disorders with psychotic features, dementia, acute mania,psychotic agitation, unipolar disorder and psychotic disorders due tospecific general medical conditions.

The methods of this invention reduce atypical antipsychotic inducedweight gain. The amount of compounds of Formula I, adequate toaccomplish this is defined as a “therapeutically effective dose”. Thedosage schedule and amounts effective for this use, i.e., the “dosingregimen,” will depend upon a variety of factors, including the type ofthe atypical antipsychotic medication the patient is using, the amountof atypical-induced weight gain that has already occurred, the patient'sphysical status, age and the like. In calculating the dosage regimen fora patient, the mode of administration also is taken into consideration.

Suitable daily oral dosages for the compounds of Formula I describedherein are on the order of about 1.0 mg to about 50 mg. Desirably, eachoral dosage contains from 1.0 to 50 mgs, particularly 1.0, 2.5, 5, 10,15, 20, 25, 30, 40 and 50 milligrams of the compounds of Formula I areadministered for the treatment atypical-induced weight gain. In apreferred embodiment, the compounds of Formula I are administered in adose range of about 3.0 mgs to about 30 mgs per day, more preferablyabout 3.0 mgs to about 15 mgs per day, even more preferably about 5 mgsper day. U.S. application Ser. No. 12/727,784, filed on Mar. 19, 2010,describing the therapeutic dosing range of carboxamide substitutedmorphinans is hereby incorporated by reference. Dosage regimen may beadjusted to provide the optimal therapeutic response. The specific doselevel for any particular patient will vary depending upon a variety offactors, including but not limited to, the activity of the specificcompound employed; the age, body weight, general health, sex and diet ofthe patient; the time of administration; the rate of excretion; drugcombination; the severity of the particular disease being treated; andthe form of administration. Typically, in vitro dosage-effect resultsprovide useful guidance on the proper doses for patient administration.Studies in animal models are also helpful. The considerations fordetermining the proper dose levels are well known in the art.

The compounds of Formula I can be administered in such oral forms astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions, syrups, and emulsions. The present invention includes theuse of both oral rapid-release and time-controlled releasepharmaceutical formulations (see, e.g., U.S. Pat. Nos.: 6,495,166;5,650,173; 5,654,008 which describes controlled release formulations andis incorporated herein by reference).

In another embodiment, the invention relates a composition comprising acompound of Formula I and an antipsychotic, preferably selected fromolanzapine, clozapine, risperidone, quetiapine, aripiprazole andziprasidone. In a more preferred embodiment, a compound of Formula I isselected from Table A. In a more preferred embodiment, the inventionrelates to a composition comprising a compound of Table A and anantipsychotic selected from olanzapine, clozapine, risperidone,quetiapine, aripiprazole and ziprasidone.

The compounds of Formula I can be administered in a mixture withpharmaceutical diluents, excipients or carriers (collectively referredto herein as “carrier” materials) suitably selected with respect to theintended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the compounds of Formula I can be combined with a non-toxic,pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, modified sugars, modified starches, methyl celluloseand its derivatives, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and other reducing and non-reducing sugars, magnesium stearate,steric acid, sodium stearyl fumarate, glyceryl behenate, calciumstearate and the like. For oral administration in liquid form, the drugcomponents can be combined with non-toxic, pharmaceutically acceptableinert carrier such as ethanol, glycerol, water and the like. Moreover,when desired or necessary, suitable binders, lubricants, disintegratingagents, coloring and flavoring agents can also be incorporated into themixture. Stabilizing agents such as antioxidants (BHA, BHT, propylgallate, sodium ascorbate, citric acid) can also be added to stabilizethe dosage forms. Other suitable components include gelatin, sweeteners,natural and synthetic gums such as acacia, tragacanth or alginates,carboxymethylcellulose, polyethylene glycol, waxes and the like. For adiscussion of dosing forms, carriers, additives, pharmacodynamics, etc.,see Kirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition,1996, 18:480-590, incorporated herein by reference.

DEFINITIONS

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g., single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, and substituted or unsubstituted cycloalkyl groupsas described herein.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted saturated aliphatic hydrocarbonradicals/groups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”) preferablyabout 7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about24 carbon atoms (“C₈-C₂₄”), preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkyl groups comprise at about 1 to about 8carbon atoms (“C₁-C₈”) such as about 1 to about 6 carbon atoms(“C₁-C₆”), or such as about 1 to about 3 carbon atoms (“C₁-C₃”).Examples of C1-C6 alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tent-butyl, n-pentyl,neopentyl and n-hexyl radicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkenyl radicals are “lower alkenyl”radicals having two to about ten carbon atoms (“C₂-C₁₀”) such asethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Preferred loweralkenyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”). The terms“alkenyl”, and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The term “hydroxyalkyl” as used herein refers to an alkyl substituent,as defined herein, wherein one or more hydrogens are replaced with an—OH group.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g., CH₃—CH₂—), or in otherinstances, a bivalent linking moiety can be “alkyl,” in which case thoseskilled in the art will understand the alkyl to be a divalent radical(e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene”.Similarly, in circumstances in which divalent moieties are required andare stated as being “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”,“aryl”, “heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”,“aliphatic”, or “cycloalkyl”, those skilled in the art will understandthat the terms alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”,“aliphatic”, or “cycloalkyl” refer to the corresponding divalent moiety.The invention is further illustrated by the following non-limitedexamples.

EXAMPLE 1: EVALUATION OF COMPOUND 1 on OLANZAPINE-RELATED WEIGHT GAIN INFEMALE RATS

To determine if Compound 1 could reduce antipsychotic associated weightgain, four groups of female rats (n=8/group) were used for thisstudy: 1) olanzapine only; 2) olanzapine and naltrexone; 3) olanzapineand Compound1; and 4) vehicle control. The rats were assigned totreatment groups using a random block design based on initial bodyweight. The olanzapine group was given PO twice daily (6 hours betweendoses) at a dose of 1 mg/kg (in 1% methylcellulose, for 10 consecutivedays). Naltrexone and Compound 1 were both administered at doses of 2mg/kg (SC) concurrent with the afternoon administration of olanzapine.There was an effect of Treatment (F_((3,28))=9.7, p<0.001), Day(F_((3,9))=359.8, p<0.001) and a Treatment×Day interaction(F_((27, 252))=10.2, p<0.001) on body weight. While all rats gainedweight during the study, olanzapine alone administration caused greaterincreases in weight gain and the increased gain was apparent by day 5.Co-administration of naltrexone with olanzapine did not affectolanzapine-induced weight gain. In contrast, weight gain in ratsreceiving Compound 1 was similar to those in vehicle-controls rats,demonstrating the ability of Compound1 to block olanzapine inducedweight gain (FIG. 1).

EXAMPLE 2: EVALUATION OF COMPOUND1 AND NALTREXONE ON CIRCULATING GHRELINLEVELS

Recent research has reported that the gut hormone ghrelin plays a rolein appetite regulation by targeting the brain to promote food intake andadiposity (Chaudhri O, et al., Philos Trans R Soc Lond B Biol Sci. 2006Jul. 29; 361(1471):1187-209; Abizaid A, et al., J. of Clin. Invest.116:3229-3239.) It is also known in literature that olanzapine increasescirculating ghrelin levels. To determine whether Compound1 andnaltrexone have any effect on circulating levels of ghrelin, conscious,unrestrained rats (low stress model) were administered Compound 1 andnalrextone (10 mg/kg, PO). Blood samples were collected and analyzed bybioanalytical for circulating levels of ghrelin at 0, 15, 30, 60, and120 minutes most administration. Results indicated that naltrexone hadsignificantly greater circulating ghrelin levels than Compound 1 twohours post administration (FIG. 2).

EXAMPLE 3: EVALUATION OF OLANZAPINE-RELATED CHANGES IN NON-HUMANPRIMATES

The purpose of the study was to evaluate if changes in body weight canbe assessed in female cynomolgus monkeys after twice daily oral (gavage)treatment with olanzapine and if changes were observed, can once a dayintramuscular co-administration of Compound 1 mitigate or attenuate anyof these changes. Clinical observations and weight gain were assessedover a 28-day treatment period.

Three groups of late-adolescent female cynomolgus monkeys (n=5/group;4.04 assessed in female cynomolgus monkeys after 120 minutes mostadmolanzapine only; and 3) olanzapine with Compound 1. Beginning twoweeks prior to the study, monkeys were given ad libitum access to ahighly palatable, high caloric diet. On the day prior to the start oftreatment, monkeys were weighed and assigned to groups using arandomized block design based on body weight (BW); average BW across the3 groups was 3.1±0.08 kg on the day of randomization. Also, baselinewhole body CT scans were taken on the day prior to initiation oftreatments. Monkeys receiving olanzapine were dosed twice daily (6 hoursbetween doses) for 28 days. The initial daily dose of olanzapine was 1mg/kg (PO, in 1% methylcellulose) and increased every 3 days to a dailydose of 6 mg/kg by Day 10. For group 3, Compound 1 (0.4 mg/kg, IM) wasadministered in the morning immediately after administration ofolanzapine. Weights were taken every 3 days and on Day 28 blood sampleswere collected for serum chemistry analysis. A second CT scan wasconducted on day 29.

Results indicated that BWs were relatively constant for two months priorto the initiation of ad libitum feeding. Vehicle treated monkeys gainedan average of 0.28 kg (9% of Day 0 BW) over the 28-day study. This gainwas attributed to the ad libitum feeding of the highly palatable diet.Over the same 28-day period, olanzapine-treated monkeys gained anaverage of 0.46 kg (15% of Day 0 BW). This marked increase in averageweight gain was driven by 3 of the 5 monkeys who gained between 19.8 and37.8% of their initial body weight. An accretion of adipose tissue wasobserved in all monkeys compared to baseline control values. However,monkeys in the olanzapine group gained relatively more adipose tissuecompared to the vehicle group. Also, there was a difference in thelocation of the adipose tissue deposition with the olanzapine groupshowing more abdominal fat accretion (FIG. 5). Concentrations oftriglycerides (TGs) and LDL were higher in olanzapine treated animals(86.6 and 105.8 mg/dL, respectively) compared to the vehicle group (62and 87.8 mg/dL, respectively) (FIG. 6). In monkeys treated witholanzapine and Compound 1, the average BW gain over the 28 days was only0.08 kg (2.6% of Day 0 BW). While these animals also gained adiposetissue, the extent and distribution of fat was similar to that observedin the vehicle group and lower than the olanzapine-only group. Finally,co-administration of Compound 1 prevented olanzapine-induced elevationsin TGs and LDL concentrations.

Based on this data, treatment of nonhuman primates with olanzapine for28 days resulted in qualitative changes in weight, adipose tissueaccretion, TGs and LDLs similar to those reported in patients.Furthermore, OLZ-induced changes were mitigated by co-administration ofCompound 1 (FIGS. 3 and 4).

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications andother references mentioned herein are hereby incorporated by referencein their entirety.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-32. (canceled)
 33. A method of treating schizophrenia, in a patient inneed thereof, where the patient has previously experienced significantweight gain induced by olanzapine treatment alone, comprisingadministering to the patient a daily dose of a pharmaceuticalcomposition comprising: olanzapine or a pharmaceutically acceptable saltthereof; and 10 mg of a compound having the structure:

or a pharmaceutically acceptable salt thereof.
 34. The method of claim33, wherein the patient on olanzapine treatment alone previously gainedat least 2% of their initial body weight after ten weeks of olanzapineadministration.
 35. The method of claim 33, wherein the patient onolanzapine treatment alone previously gained at least 5% of theirinitial body weight after ten weeks on olanzapine administration. 36.The method of claim 1, wherein the pharmaceutical composition is atablet.
 37. The method of claim 1, wherein the compound is present inthe pharmaceutical composition as a pharmaceutically acceptable salt.38. The method of claim 33, wherein the weight gain induced byolanzapine treatment alone is mitigated by the co-administration of apharmaceutical composition comprising: olanzapine or a pharmaceuticallyacceptable salt thereof; and 10 mg of a compound having the structure:

or a pharmaceutically acceptable salt thereof.
 39. The method of claim38, wherein the compound is present in the pharmaceutical composition asa pharmaceutically acceptable salt.
 40. A method of treatingschizophrenia, in a patient in need thereof, wherein the significantweight gain induced by olanzapine treatment alone is mitigated by theco-administration of a daily dose of a pharmaceutical compositioncomprising: olanzapine or a pharmaceutically acceptable salt thereof;and 10 mg of a compound having the structure:

or a pharmaceutically acceptable salt thereof.
 41. The method of claim40, wherein the compound is present in the pharmaceutical composition asa pharmaceutically acceptable salt.